5V47

Crystal structure of the SR1 domain of lizard sacsin

Summary for 5V47

• Entry DOI: 10.2210/pdb5v47/pdb
• Related: 5V44 5V45 5V46
• Descriptor: Lizard sacsin, SULFATE ION (3 entities in total)
• Functional Keywords: alpha-beta sandwich, bergerat fold, chaperone
• Biological source: Anolis carolinensis (Green anole)
• Total number of polymer chains: 2
• Total formula weight: 57598.17

Authors

Pan, T.,Menade, M.,Kozlov, G.,Gehring, K. (deposition date: 2017-03-08, release date: 2017-05-24, Last modification date: 2023-10-04)

Primary citation

Menade, M.,Kozlov, G.,Trempe, J.F.,Pande, H.,Shenker, S.,Wickremasinghe, S.,Li, X.,Hojjat, H.,Dicaire, M.J.,Brais, B.,McPherson, P.S.,Wong, M.J.H.,Young, J.C.,Gehring, K.
Structures of ubiquitin-like (Ubl) and Hsp90-like domains of sacsin provide insight into pathological mutations.
J. Biol. Chem., 293:12832-12842, 2018

PubMed Abstract: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a neurodegenerative disease that is caused by mutations in the gene. The product of this gene is a very large 520-kDa cytoplasmic protein, sacsin, with a ubiquitin-like (Ubl) domain at the N terminus followed by three large sacsin internal repeat (SIRPT) supradomains and C-terminal J and HEPN domains. The SIRPTs are predicted to contain Hsp90-like domains, suggesting a potential chaperone activity. In this work, we report the structures of the Hsp90-like Sr1 domain of SIRPT1 and the N-terminal Ubl domain determined at 1.55- and 2.1-Å resolutions, respectively. The Ubl domain crystallized as a swapped dimer that could be relevant in the context of full-length protein. The Sr1 domain displays the Bergerat protein fold with a characteristic nucleotide-binding pocket, although it binds nucleotides with very low affinity. The Sr1 structure reveals that ARSACS-causing missense mutations (R272H, R272C, and T201K) disrupt protein folding, most likely leading to sacsin degradation. This work lends structural support to the view of sacsin as a molecular chaperone and provides a framework for future studies of this protein.

PubMed: 29945973
DOI: 10.1074/jbc.RA118.003939

Experimental method

X-RAY DIFFRACTION (1.84 Å)